Abstract Stroke is a leading cause of morbidity and mortality in the United States. However less than 10% of patients are eligible for the current approved interventions of tissue plasminogen activator or thrombectomy. We seek to develop new therapeutics to reduce the extent of damage and functional impairment resulting from ischemic injury to the brain, an area of significant unmet medical need. We have found that interferon regulatory factor (IRF) mediated gene transcription may represent an endogenous mechanism of neuroprotection that is associated with a reduction in ischemic injury. Using both cell and mouse models of stroke we have demonstrated that administration of compounds following the ischemic insult, that are known to induce IRF mediated gene transcription, significantly reduces the extent of damage. These results indicate that activation of IRF transcription factors following stroke may be a viable therapeutic intervention for the treatment of stroke patients. The ultimate goal of this STTR program is to identify compounds that induce IRF transcription in both mouse and human cells but with minimal off-target immune activity. We will identify compounds with acceptable target specification, optimize these compounds through hit to lead protocols and ultimately test for efficacy in a mouse model of cerebral ischemic injury. We propose the following aims: Aim 1: Identify lead compounds for therapeutic development of an acute neuroprotectant using an experimentally validated high throughput screening platform. Aim 2: Evaluate and rank lead compounds through hit to lead characterization. Aim 3: Evaluate PK and tolerability of lead compounds and determine efficacy in a mouse model of cerebral ischemic injury.